The invention relates to “active medical devices” as defined by Council of the European Communities Directive 90/385/EEC of 20 Jun. 1990.
It relates more specifically to implants making it possible to deliver, i.e. to administer, Functional Electrical Stimulation (FES) therapies, consisting in applying stimulation in the form of repeated electric pulses to organs for therapeutic purposes.
The invention relates more particularly to implants making it possible to deliver therapies for stimulating biological tissues. The invention relates more specifically to stimulating the nervous system (such stimulation being generally referred to below as “neurostimulation”), particularly but non-limitingly Vagus Nerve Stimulation (VNS), by means of a device comprising a lead provided with an electrode implanted on the vagus nerve or in the vicinity thereof, and a generator that delivers VNS electric pulses to said electrode.
EP 2 926 863 A1 (Sorin CRM) describes such a VNS generator for stimulating the vagus nerve.
However, such use is not limiting, and the invention is applicable to other situations in which biological tissue stimulation requires compensation pulses to be delivered.
Stimulating the nervous system is a therapeutic approach that is recognized or that is being evaluated for a large number of disorders such as epilepsy, major depression, pain, heart failure, sleep apnea, obesity, etc. VNS has demonstrated positive effects in preclinical trials for heart failure, where it acts on the autonomic nervous system, and, in secondary manner, on the cardiovascular functions, inducing a reduction in the heart rate and an increase in the ejection fraction of the left ventricle, thereby, in particular, making it possible to contribute to reducing the progress of cardiac remodeling that can give rise to a state of worsened heart failure.
Through its action on the sympathovagal balance (SVB) of the patient, neurostimulation also has a general effect on the vascular system, with vasoconstriction being modulated by modifying the diameters of the arteries and the peripheral resistance, resulting in a general vasodilation of the vascular system.
The neurostimulation pulses may optionally be delivered synchronously with the heart rate or with any other physiological parameter, in which case the device comprises means for collecting at least one physiological parameter, typically myocardial depolarization waves, which can be measured by collecting an electrocardiogram (ECG) using a subcutaneous electrode, an electrogram (EGM) using an electrode implanted on or in the myocardium, or a far-field signal collected between the housing and an electrode placed outside the heart, in particular a pole of the neurostimulation electrode placed on or in the vicinity of a nervous structure.
Since neurostimulation pulses are current pulses, when physiological tissue is stimulated, the interface between the electrode and the tissue should remain generally balanced in terms of electric charge.
With constant-current pulses, charge Q is defined as the product of the current I (in amps (A) or milliamps (mA)) multiplied by the duration or width PW of the pulse (in seconds (s) or milliseconds (ms)): Q=I×PW, and is therefore expressed in coulombs, or more generally in microcoulombs (μC) in neurostimulation.
Since, due to the current flowing, delivery of the neurostimulation pulse proper (referred to below as the “stimulation phase”) produces a creation and an accumulation of charge at the stimulation site, that charge needs to be compensated for or cancelled out by an opposite charge (by causing a current to flow in the direction opposite to the direction of the stimulation phase), in such a manner as to maintain the overall electrical neutrality of the stimulated tissue.
US2010/0114198 A1 describes a stimulation pulse generator incorporating a circuit that automatically performs such charge compensation.
The opposite compensation charge (referred to below as the “compensatory phase”) may take place:                passively, by a spontaneous discharge in the bioimpedance formed by the tissues at the stimulation site, this discharge (referred to below as “passive discharge”) taking place after applying an isolated stimulation pulse or a burst of successive stimulation pulses; and/or        actively, by a charge resulting from a current pulse generated by the stimulator and applied to the tissue before (pre-charge) or after (“post-charge”) one or more stimulation pulses.        
Such a combination of time phases comprising i) a stimulation phase and ii) a compensatory phase comprising at least one active pre-charge/post-charge or a final passive discharge is referred to as a “multi-phase pulse train”.
The term “pre-charge pulse” is used below to designate a type of controlled compensatory pulse, but that term does not presuppose any particular type of multi-phase sequence of pulses, it being possible for the controlled compensatory phase to be generated not only before but also after a stimulation phase, regardless of whether said stimulation phase is formed of an isolated stimulation pulse or of a burst of stimulation pulses succeeding one another at a high rate.
In addition, various multi-phase profiles combining pre-charge and stimulation pulses may be considered, e.g. with a pre-charge pulse associated with each stimulation pulse, or a pre-charge pulse associated with a plurality of successive stimulation pulses, etc. it being specified that the invention is applicable to any type of stimulation profile combining a pre-charge (or post-charge) pulse, one or more stimulation pulse(s), and a passive discharge pulse. The invention is applicable to any type of multi-phase stimulation implementing the various pre-charge or post-charge, stimulation and passive discharge time phases, in particular neurostimulation. In the remainder of the document, reference is made to pre-charging, but the invention may be applied in similar manner to post-charging.
In any event, the pre-charge phase comprises applying a current pulse of opposite direction to the direction of current of the stimulation pulse, and of controlled amplitude and controlled duration, in order to produce a total charge −Q equal but opposite to the charge Q of the stimulation.
To prevent the pre-charge from producing physiological effects, the amplitude of the pre-charge pulse is adjusted to a level that is much lower than the level of a simulation pulse, its duration or width being extended so that the corresponding quantity of charge (equal to the product of the current multiplied by the duration or width of the pulse) is of the same order of magnitude as the stimulation charge to be compensated. For example, a stimulation pulse of 3 mA/0.5 ms is compensated for by a pre-charge pulse of 0.5 mA/3 ms.
The aim of a stimulator producing such multi-phase pulse trains is to obtain the expected physiological effects, e.g. a reduction in heart rate, a controlled modification in the sympathovagal balance, etc. while also maintaining an overall balance of electric charges at the end of the pulse train. However, only the stimulation should produce a physiological effect, the compensatory phases (pre-charge, post-charge, passive discharge) should not be effective physiologically.
In such a situation, the main problem is to make sure that the compensatory phases (pre-charge(s) and passive discharge) do not produce undesirable physiological effects.
Unfortunately, nerves, in particular the vagus nerve, which is often the target of neurostimulation therapy, are made up of a very large number of nerve fibers of different types (types A, B, and C in particular for the vagus nerve), each type of fiber having its own characteristics as regards activation threshold and velocity of propagation of the nerve impulse. Thus, the thickest fibers have a low activation threshold and a high velocity of propagation, while the thinnest fibers have the reverse properties.
The compensatory phases can thus produce certain physiological effects due to the pulse being captured by certain nerve fibers, and potentially those that have the lowest excitation threshold. It is also necessary to take account of the fact that the fibers that are shallowest, close to the electrodes, receive more current than the same fibers that are situated deep in the nerve, and can therefore also be activated even if their excitation threshold is higher.